Vonoprazan; amoxicillin is a co-packaged oral product containing vonoprazan, a potassium-competitive acid blocker (PCAB) with amoxicillin, a penicillin class antibacterial. The product is indicated for the treatment of Helicobacter pylori (H. pylori) infection in adults. During clinical trials, treatment-naive H. pylori-positive adult patients with at least one of the following clinical conditions were candidates: dyspepsia lasting for at least 2 weeks, functional dyspepsia, recent or new diagnosis of peptic ulcer, peptic ulcer not treated for H. pylori infection, or a stable dose of long-term NSAID treatment. H. pylori eradication was confirmed with a negative urea breath test at 27 days or more post-therapy. The vonoprazan; amoxicillin dual therapy product was shown to be noninferior to LAC (standard lansoprazole, amoxicillin, clarithromycin H. pylori regimen) in patients who did not have a clarithromycin or amoxicillin resistant strain of H. pylori at baseline. The vonoprazan; amoxicillin dual therapy product was shown to be superior to LAC in patients who had a clarithromycin resistant strain of H. pylori at baseline and in the overall population. Vonoprazan; amoxicillin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. Vonoprazan reduces intragastric acidity and can affect the oral absorption of certain oral medications, leading to changes in safety and/or effectiveness; review drug interactions. Appropriate treatment of H. pylori reduces symptoms, improves gastric healing, helps prevent future ulceration, and reduces the risk of complications from peptic ulcer disease (e.g., bleeding). The vonoprazan; amoxicillin dual therapy product was FDA approved in May 2022.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-Administer vonoprazan twice daily (in the morning and evening) and amoxicillin three times daily (in the morning, mid-day, and evening). Vonoprazan tablets and amoxicillin capsules are supplied in separate blister cavities within the same blister card for the needed doses each day. Each treatment pack contains 14 blister cards; one blister card for each day of the 14-day regimen.
-Administer with or without food.
-Missed dose: If a dose is missed, administer the missed dose as soon as possible, within 4 hours after the missed dose. If more than 4 hours have passed, skip the missed dose and administer the next dose on the regularly scheduled time. Patients should continue the normal dosing schedule until the medication is completed.
Hypersensitivity and dermatologic reactions may occur with the use of vonoprazan; amoxicillin dual pack. Drug hypersensitivity, rash, dermatitis, and xerosis (dry skin) were reported in less than 2% of patients receiving vonoprazan; amoxicillin dual pack during clinical trials. The most common adverse reaction leading to discontinuation of vonoprazan; amoxicillin dual pack was rash (0.6%). Vonoprazan has been reported to cause hypersensitivity or dermatologic reactions during postmarketing use such as anaphylactic shock, urticaria, drug eruption, erythema multiforme, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Dermatologic or hypersensitivity reactions reported clinically since marketing with amoxicillin include serum sickness-like reactions, erythematous maculopapular rash, erythema multiforme, exfoliative dermatitis, urticaria, SJS, TEN, acute generalized exanthematous pustulosis (AGEP), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), hypersensitivity vasculitis, Henoch-Schonlein purpura (IgA vasculitis), and linear IgA bullous dermatosis. Penicillin allergy has been reported in up to 20% of patients receiving penicillin-class antibiotics; however, around 90% of reported allergies are incorrectly reported and many patients lack penicillin-specific IgE antibodies. The actual prevalence of penicillin allergy is likely no greater than 5%. The severity of these reactions range from a benign rash to anaphylactoid reactions, angioedema, or anaphylactic shock. If hypersensitivity is suspected or a skin reaction occurs, discontinue vonoprazan; amoxicillin dual pack and institute appropriate evaluation and treatment.
The most common gastrointestinal (GI) adverse reactions reported with vonoprazan; amoxicillin dual pack use during clinical trials diarrhea (5.2%), abdominal pain (2.6%), and dysgeusia or taste disorder (0.6%). Other GI adverse reactions occurring in less than 2% of patients included decreased appetite (anorexia), abdominal distension, constipation, dry mouth (xerostomia), peptic ulcer (duodenal or gastric ulcer), dyspepsia, flatulence, gastroesophageal reflux disease, nausea and/or vomiting, hematochezia, duodenal polyp, large intestine polyp, rectal polyp, stomatitis, tongue discomfort. GI adverse effects that have been reported with amoxicillin use postmarketing include black hairy tongue (tongue discoloration) and colitis accompanied by GI bleeding (hemorrhagic colitis).
Microbial overgrowth and superinfection can occur with antibiotic use. Vaginal candidiasis (inclusive of urogenital infection fungal, vulvovaginal candidiasis, vulvovaginal mycotic infection, vulvovaginal pruritus, genital pruritus, genital infection fungal) was reported in 2% of patients taking vonoprazan; amoxicillin dual pack during clinical trials. Naso-pharyngitis was reported in 2% of treated patients. Infections reported in less than 2% of treated patients included anal fungal infection, gastrointestinal viral infection, oral fungal infection, pneumonia, tongue fungal infection, upper respiratory tract infection, urinary tract infection, and viral infection. Mucocutaneous candidiasis has been reported with postmarketing use of amoxicillin. The use of gastric acid suppressive therapy, such as vonoprazan, may increase the risk of enteric infection or superinfection by encouraging the growth of gut microflora. C. difficile-associated diarrhea (CDAD) or pseudomembranous colitis has been reported with amoxicillin use, and may occur during or following completion of treatment. CDAD may range in severity from mild diarrhea to fatal colitis or a need for colectomy. If pseudomembranous colitis is suspected or confirmed, ongoing antibacterial therapy not directed against C. difficile may need to be discontinued. Institute appropriate fluid and electrolyte management, protein supplementation, C. difficile-directed antibacterial therapy, and surgical evaluation as clinically appropriate.
Hematologic adverse reactions occurring in less than 2% of patients treated with vonoprazan; amoxicillin dual pack include anemia, leukocytosis, leukopenia, and neutropenia. Amoxicillin and other penicillin-class antibiotics have been reported to cause hemolytic anemia, thrombocytopenia, thrombotic thrombocytopenic purpura (TTP), eosinophilia, and agranulocytosis; these reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena.
Headache was reported in 1.4% of patients treated during clinical trials with vonoprazan; amoxicillin dual pack. Central nervous system adverse events that have been reported in less than 2% of patients treated with vonoprazan; amoxicillin dual pack include ageusia, dizziness, and tension headache. Psychiatric disorders reported in less than 2% of treated patients include anxiety, depression, and insomnia. Reversible hyperactivity, agitation, confusion, convulsions or seizures, aseptic meningitis, and behavioral changes have rarely been reported with the use of amoxicillin postmarketing.
Hypertension or increased blood pressure was reported in 1.1% of patients treated with vonoprazan; amoxicillin dual pack during clinical trials.
Orbital edema (blepharedema and other edema around the eyes) was reported in less than 2% of patients treated with vonoprazan; amoxicillin dual pack during clinical trials.
General adverse reactions reported in less than 2% of patients treated with vonoprazan; amoxicillin dual pack during clinical trials included fatigue and pyrexia (increased body temperature or fever).
Elevated hepatic enzymes were reported in less than 2% of patients treated with vonoprazan; amoxicillin dual pack during clinical trials. Hepatic adverse events that have been reported in patients receiving vonoprazan postmarketing have included hepatic injury, hepatic failure, and jaundice.
Musculoskeletal adverse reactions reported in less than 2% of patients treated with vonoprazan; amoxicillin dual pack during clinical trials included bone fractures.
Renal and urinary tract adverse reactions reported in less than 2% of patients treated with vonoprazan; amoxicillin dual pack during clinical trials included renal hypertrophy and tubulo-interstitial nephritis. Crystalluria has been reported with the postmarketing use of amoxicillin.
Reproductive and breast system disorders reported in less than 2% of patients treated with vonoprazan; amoxicillin dual pack included vaginal discharge.
Respiratory, thoracic, and mediastinal disorders reported in less than 2% of patients treated with vonoprazan; amoxicillin dual pack included cough, nasal polyps, and oropharyngeal pain.
Tooth discoloration (brown, yellow, or gray staining) has rarely been reported with amoxicillin therapy postmarketing. The majority of reports have been in children. In most cases, discoloration was reduced or eliminated by brushing or dental cleaning.
Drug-induced enterocolitis syndrome (DIES) has been reported with amoxicillin use. Most cases occur in pediatric patients. DIES is a non-IgE mediated hypersensitivity reaction characterized by protracted vomiting occurring 1 to 4 hours after drug ingestion in the absence of skin or respiratory symptoms. DIES may be associated with pallor, lethargy, hypotension, shock, and diarrhea within 24 hours after ingesting amoxicillin as well as leukocytosis with neutrophilia. If DIES occurs, discontinue vonoprazan; amoxicillin and institute appropriate therapy.
Vonoprazan; amoxicillin dual pack is contraindicated for use with rilpivirine-containing products. Review drug interactions prior to prescribing.
This product contains amoxicillin, a penicillin, and is contraindicated in patients who have a history of severe hypersensitivity reactions to beta-lactam antibiotics (i.e., penicillin hypersensitivity, cephalosporin hypersensitivity, and carbapenem hypersensitivity). Patients who have a hypersensitivity to vonoprazan are also contraindicated to receive this product. Serious and occasionally fatal reactions (e.g., anaphylaxis) have been reported with the components of this product. Severe cutaneous adverse reactions (SCAR) have also been reported. Discontinue this dual pack at the first signs or symptoms of a serious rash and consider further evaluation. If hypersensitivity reactions occur, discontinue vonoprazan; amoxicillin dual pack and institute immediate therapy (e.g., anaphylaxis management).
A high percentage of patients with mononucleosis who receive amoxicillin develop an erythematous skin rash. Avoid use of vonoprazan; amoxicillin dual pack in patients with mononucleosis.
Consider pseudomembranous colitis in patients presenting with diarrhea during or after vonoprazan; amoxicillin use. Careful medical history is necessary, as pseudomembranous colitis has been reported to occur over 2 months after the administration of antibacterial agents. Almost all antibacterial agents have been associated with pseudomembranous colitis or C. difficile-associated diarrhea (CDAD) which may range in severity from mild to life-threatening. Treatment with antibacterial agents alters the normal flora of the colon, leading to overgrowth of C. difficile. Acid suppressive therapy may also be associated with an increased risk of C. difficile-associated diarrhea (CDAD), especially in hospitalized patients. If CDAD is confirmed, discontinue vonoprazan; amoxicillin dual pack. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
Avoid use of vonoprazan; amoxicillin dual pack in patients with severe renal impairment (eGFR less than 30 mL/minute) or renal failure. The pack does not allow for appropriate dosage adjustments needed for these patients.
Avoid use of vonoprazan; amoxicillin dual pack in patients with moderate or severe (Child-Pugh B or C) hepatic disease. No dosage adjustment is needed for patients with mild hepatic impairment (Child-Pugh A).
There are no adequate and well-controlled studies of vonoprazan; amoxicillin dual pack during pregnancy or in pregnant women to evaluate for drug-associated risks of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. No reproductive and developmental toxicity studies with the combination of vonoprazan and amoxicillin were conducted. Avoid use of vonoprazan; amoxicillin during pregnancy unless other treatments are not clinically appropriate. Except in very unusual cases, H. pylori eradication treatment can generally be deferred until after delivery. For amoxicillin, available data from published epidemiologic studies and pharmacovigilance over several decades have not established drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes. For vonoprazan, there are only limited animal data. In pregnant rats, no adverse effects were noted after oral administration of vonoprazan during organogenesis at approximately 27-times the maximum recommended human dose (MRHD) based on AUC exposure comparisons. In a pre- and postnatal development (PPND) study, pups from dams orally administered vonoprazan during organogenesis and through lactation, exhibited liver discoloration, which in follow-up mechanistic animal studies was associated with necrosis, fibrosis and hemorrhage at a dose approximately 22-times the MRHD based on AUC comparisons which were likely attributable to exposure during lactation. These effects were not observed at the next lower dose in this study, which was approximately equal to the MRHD based on AUC comparison, however they were seen at clinically relevant exposures in dose-range finding studies in rats. The manufacturer requests that pregnancy exposures be reported to the Phathom Pharmaceuticals, Inc. Adverse Event reporting line at 1-888-775-PHAT (7428).
There are no data regarding the presence of vonoprazan in humans while breast-feeding, the effects on the breastfed infant or the effects on milk production. Vonoprazan and its metabolites are present in rat milk. Liver injury occurred in offspring from pregnant and lactating rats administered oral vonoprazan at AUC exposures approximately equal to and greater than the maximum recommended human dose (MRHD). When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because of the potential risk of adverse liver effects shown in animal studies with vonoprazan, a woman should pump and discard human milk for the duration of vonoprazan; amoxicillin dual pack therapy, and for 2 days after therapy ends, and feed her infant stored human milk (collected prior to therapy) or formula.
Administration of vonoprazan; amoxicillin dual pack may result in diagnostic or laboratory test interference. High urine concentrations of amoxicillin may cause false-positive results when using glucose tests based on the Benedict's copper reduction reaction that determines the amount of reducing substances like glucose in the urine. Use a test based on enzymatic glucose oxidase reactions when testing for glucose in the urine of patients treated with this product. Vonoprazan reduces intragastric acidity, which increases chromogranin A (CgA) levels and may cause false positive results in diagnostic investigations for neuroendocrine tumors. Assess CgA levels at least 14 days after dual pack treatment and repeat the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), use the same commercial laboratory for testing, as reference ranges between tests may vary.
The safety and efficacy of vonoprazan; amoxicillin dual pack have not been established in children and infants below 18 years of age.
Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: Helicobacter pylori
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.
For Helicobacter pylori (H. pylori) eradication:
Oral dosage:
Adults: 20 mg vonoprazan PO twice daily and 1,000 mg amoxicillin PO three times daily for 14 days.
Maximum Dosage Limits:
-Adults
Vonoprazan 40 mg/day PO; amoxicillin 3,000 mg/day PO.
-Geriatric
Vonoprazan 40 mg/day PO; amoxicillin 3,000 mg/day PO.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Mild hepatic impairment (Child-Pugh A): No dosage adjustment is needed.
Moderate to severe hepatic impairment (Child-Pugh B or C): Avoid use.
Patients with Renal Impairment Dosing
Mild to moderate renal impairment (eGFR 30 to 89 mL/minute/1.73 m2): No dosage adjustment is needed.
Severe renal impairment (eGFR less than 30 mL/minute/1.73 m2): Avoid use.
*non-FDA-approved indication
Acalabrutinib: (Major) Avoid concomitant use of acalabrutinib and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of acalabrutinib reducing its efficacy.
Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Acetaminophen; Aspirin: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Acetaminophen; Aspirin; Diphenhydramine: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Consider a reduced dose of dihydrocodeine with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. If vonoprazan is discontinued, consider increasing the dihydrocodeine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Concomitant use of dihydrocodeine with vonoprazan may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If vonoprazan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Vonoprazan is a weak inhibitor of CYP3A, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with vonoprazan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of vonoprazan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If vonoprazan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Vonoprazan is a weak inhibitor of CYP3A.
Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like vonoprazan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If vonoprazan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. If vonoprazan is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with weak CYP3A inhibitors like vonoprazan can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If vonoprazan is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Albuterol; Budesonide: (Moderate) Monitor for altered response to budesonide in patients receiving vonoprazan with enteric-coated or extended-release formulations of oral budesonide. Enteric-coated budesonide granules (Entocort EC) dissolve at a pH greater than 5.5. Likewise, the dissolution of the coating of extended-release budesonide tablets (Uceris) is pH dependent. Concomitant use of oral budesonide and drugs that increase gastric pH levels, such as vonoprazan, can cause these products to dissolve prematurely, possibly affecting release properties and absorption of the drug in the duodenum.
Alfentanil: (Moderate) Consider a reduced dose of alfentanil with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. If vonoprazan is discontinued, consider increasing the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Alfentanil is a sensitive CYP3A substrate, and coadministration with CYP3A inhibitors like vonoprazan can increase alfentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of alfentanil. If vonoprazan is discontinued, alfentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to alfentanil.
Allopurinol: (Minor) Use of amoxicillin with allopurinol can increase the incidence of drug-related skin rash.
Alprazolam: (Major) Avoid coadministration of alprazolam and vonoprazan due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. If coadministration is necessary, consider reducing the dose of alprazolam as clinically appropriate and monitor for an increase in alprazolam-related adverse reactions. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with vonoprazan, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor. Coadministration with another weak CYP3A inhibitor increased alprazolam maximum concentration by 82%, decreased clearance by 42%, and increased half-life by 16%.
Amobarbital: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Amphetamine: (Major) Avoid concomitant use of amphetamines and vonoprazan. Vonoprazan reduces intragastric acidity, which may increase the exposure of amphetamines and risk of toxicity.
Amphetamine; Dextroamphetamine Salts: (Major) Avoid concomitant use of amphetamines and vonoprazan. Vonoprazan reduces intragastric acidity, which may increase the exposure of amphetamines and risk of toxicity.
Amphetamine; Dextroamphetamine: (Major) Avoid concomitant use of amphetamines and vonoprazan. Vonoprazan reduces intragastric acidity, which may increase the exposure of amphetamines and risk of toxicity.
Apalutamide: (Major) Avoid concomitant use of vonoprazan and apalutamide due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and apalutamide is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Aripiprazole: (Moderate) Monitor for aripiprazole-related adverse reactions during concomitant use of vonoprazan. Patients receiving both a CYP2D6 inhibitor plus vonoprazan may require an aripiprazole dosage adjustment. Dosing recommendations vary based on aripiprazole dosage form, CYP2D6 inhibitor strength, and CYP2D6 metabolizer status. See prescribing information for details. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is a CYP3A and CYP2D6 substrate; vonoprazan is a weak CYP3A inhibitor.
Aspirin, ASA: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer. (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Aspirin, ASA; Caffeine: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Aspirin, ASA; Caffeine; Orphenadrine: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with vonoprazan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of vonoprazan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If vonoprazan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Vonoprazan is a weak inhibitor of CYP3A. (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Aspirin, ASA; Dipyridamole: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Aspirin, ASA; Omeprazole: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. If vonoprazan is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with weak CYP3A inhibitors like vonoprazan can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If vonoprazan is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone. (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Atazanavir: (Major) Avoid concomitant use of atazanavir and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of atazanavir reducing its efficacy.
Atazanavir; Cobicistat: (Major) Avoid concomitant use of atazanavir and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of atazanavir reducing its efficacy.
Barbiturates: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Belzutifan: (Moderate) Monitor for anemia and hypoxia if concomitant use of vonoprazan with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and vonoprazan is a CYP2C19 inhibitor.
Benzhydrocodone; Acetaminophen: (Moderate) Consider a reduced dose of benzhydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a CYP3A substrate, and coadministration with weak CYP3A inhibitors like vonoprazan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of benzhydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If vonoprazan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to benzhydrocodone.
Bexarotene: (Major) Avoid concomitant use of vonoprazan and bexarotene due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and bexarotene is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Minor) Consider additional monitoring or alternative antimicrobial therapy for patients with infections in which clinical response is highly dependent upon the rapid, bactericidal activity of penicillins. Bacterostatic antibacterials like tetracyclines may antagonize the bactericidal effects of penicillins which may reduce their efficacy. The clinical relevance of this interaction is poorly defined and for many infections the benefits of combination therapy are likely to outweigh the potential risks.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Minor) Consider additional monitoring or alternative antimicrobial therapy for patients with infections in which clinical response is highly dependent upon the rapid, bactericidal activity of penicillins. Bacterostatic antibacterials like tetracyclines may antagonize the bactericidal effects of penicillins which may reduce their efficacy. The clinical relevance of this interaction is poorly defined and for many infections the benefits of combination therapy are likely to outweigh the potential risks.
Bosentan: (Major) Avoid concomitant use of vonoprazan and bosentan due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and bosentan is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Budesonide: (Moderate) Monitor for altered response to budesonide in patients receiving vonoprazan with enteric-coated or extended-release formulations of oral budesonide. Enteric-coated budesonide granules (Entocort EC) dissolve at a pH greater than 5.5. Likewise, the dissolution of the coating of extended-release budesonide tablets (Uceris) is pH dependent. Concomitant use of oral budesonide and drugs that increase gastric pH levels, such as vonoprazan, can cause these products to dissolve prematurely, possibly affecting release properties and absorption of the drug in the duodenum.
Budesonide; Formoterol: (Moderate) Monitor for altered response to budesonide in patients receiving vonoprazan with enteric-coated or extended-release formulations of oral budesonide. Enteric-coated budesonide granules (Entocort EC) dissolve at a pH greater than 5.5. Likewise, the dissolution of the coating of extended-release budesonide tablets (Uceris) is pH dependent. Concomitant use of oral budesonide and drugs that increase gastric pH levels, such as vonoprazan, can cause these products to dissolve prematurely, possibly affecting release properties and absorption of the drug in the duodenum.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Monitor for altered response to budesonide in patients receiving vonoprazan with enteric-coated or extended-release formulations of oral budesonide. Enteric-coated budesonide granules (Entocort EC) dissolve at a pH greater than 5.5. Likewise, the dissolution of the coating of extended-release budesonide tablets (Uceris) is pH dependent. Concomitant use of oral budesonide and drugs that increase gastric pH levels, such as vonoprazan, can cause these products to dissolve prematurely, possibly affecting release properties and absorption of the drug in the duodenum.
Bupivacaine; Lidocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with vonoprazan is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Buprenorphine: (Moderate) Concomitant use of buprenorphine and vonoprazan can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when vonoprazan is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping vonoprazan, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If vonoprazan is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and vonoprazan is a CYP3A inhibitor.
Buprenorphine; Naloxone: (Moderate) Concomitant use of buprenorphine and vonoprazan can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when vonoprazan is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping vonoprazan, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If vonoprazan is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and vonoprazan is a CYP3A inhibitor.
Butalbital; Acetaminophen: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Butalbital; Acetaminophen; Caffeine: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer. (Moderate) Concomitant use of codeine with vonoprazan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of vonoprazan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If vonoprazan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Vonoprazan is a weak inhibitor of CYP3A.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer. (Moderate) Concomitant use of codeine with vonoprazan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of vonoprazan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If vonoprazan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Vonoprazan is a weak inhibitor of CYP3A. (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Cabotegravir; Rilpivirine: (Contraindicated) Concomitant use of vonoprazan with rilpivirine is contraindicated due to the potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Vonoprazan reduces intragastric acidity, which may decrease the absorption of rilpivirine reducing its efficacy.
Caffeine; Sodium Benzoate: (Moderate) Antibiotics that undergo tubular secretion such as penicillins may compete with phenylacetlyglutamine and hippuric acid for active tubular secretion. The overall usefulness of sodium benzoate; sodium phenylacetate is due to the excretion of its metabolites. An increase in metabolite concentrations could contribute to failed treatment and worsening of the patient's clinical status. This combination should be used with caution.
Carbamazepine: (Major) Avoid concomitant use of vonoprazan and carbamazepine due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Concomitant use may also increase carbamazepine concentrations. Vonoprazan is a CYP3A substrate and weak CYP3A inhibitor and carbamazepine is a CYP3A substrate and strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Cefpodoxime: (Moderate) Monitor for altered response to cefpodoxime if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of cefpodoxime reducing its efficacy.
Cefuroxime: (Major) Avoid concomitant use of cefuroxime and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of cefuroxime reducing its efficacy.
Celecoxib; Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with vonoprazan is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of vonoprazan, a weak CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Cenobamate: (Major) Avoid concomitant use of vonoprazan and cenobamate due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and cenobamate is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with vonoprazan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of vonoprazan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If vonoprazan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Vonoprazan is a weak inhibitor of CYP3A.
Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like vonoprazan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If vonoprazan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Choline Salicylate; Magnesium Salicylate: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as penicillins, and sulfonamides. An enhanced effect of the displaced drug may occur.
Cilostazol: (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with vonoprazan and monitor for an increase in cilostazol-related adverse reactions. Concurrent use may increase cilostazol exposure. Cilostazol is a CYP2C19 substrate and vonoprazan is a CYP2C19 inhibitor. Coadministration with another CYP2C19 inhibitor did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%.
Cisapride: (Major) Avoid concomitant use of cisapride and vonoprazan; use increases cisapride exposure and the risk for adverse effects such as QT/QTc prolongation and torsade de pointes (TdP). Cisapride is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor. Concomitant use of cisapride with CYP3A inhibitors is disallowed under the Propulsid Limited Access Program.
Citalopram: (Moderate) Limit the dose of citalopram to 20 mg/day if coadministered with vonoprazan. Concurrent use may increase citalopram exposure increasing the risk of QT prolongation or serotonin-related side effects. Citalopram is a sensitive CYP2C19 substrate and vonoprazan is a CYP2C19 inhibitor.
Clopidogrel: (Moderate) Monitor for reduced clopidogrel efficacy during concomitant use of vonoprazan. Clopidogrel is primarily metabolized to its active metabolite by CYP2C19 and vonoprazan is a CYP2C19 inhibitor.
Clozapine: (Moderate) Consider a clozapine dose reduction if coadministered with vonoprazan and monitor for adverse reactions. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A and vonoprazan is a weak CYP3A inhibitor. If vonoprazan is discontinued, monitor for lack of clozapine effect and increase dose if necessary.
Codeine: (Moderate) Concomitant use of codeine with vonoprazan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of vonoprazan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If vonoprazan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Vonoprazan is a weak inhibitor of CYP3A.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with vonoprazan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of vonoprazan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If vonoprazan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Vonoprazan is a weak inhibitor of CYP3A.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with vonoprazan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of vonoprazan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If vonoprazan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Vonoprazan is a weak inhibitor of CYP3A.
Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with vonoprazan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of vonoprazan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If vonoprazan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Vonoprazan is a weak inhibitor of CYP3A.
Codeine; Promethazine: (Moderate) Concomitant use of codeine with vonoprazan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of vonoprazan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If vonoprazan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Vonoprazan is a weak inhibitor of CYP3A.
Cyclosporine: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with vonoprazan is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Dabrafenib: (Major) Avoid concomitant use of vonoprazan and dabrafenib due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and dabrafenib is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Dacomitinib: (Major) Avoid concomitant use of dacomitinib and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of dacomitinib reducing its efficacy.
Dasatinib: (Major) Avoid concomitant use of dasatinib and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of dasatinib reducing its efficacy.
Demeclocycline: (Minor) Consider additional monitoring or alternative antimicrobial therapy for patients with infections in which clinical response is highly dependent upon the rapid, bactericidal activity of penicillins. Bacterostatic antibacterials like tetracyclines may antagonize the bactericidal effects of penicillins which may reduce their efficacy. The clinical relevance of this interaction is poorly defined and for many infections the benefits of combination therapy are likely to outweigh the potential risks.
Desogestrel; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Dextroamphetamine: (Major) Avoid concomitant use of amphetamines and vonoprazan. Vonoprazan reduces intragastric acidity, which may increase the exposure of amphetamines and risk of toxicity.
Diazepam: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with vonoprazan is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A and CYP2C19 substrate and vonoprazan is a CYP3A and CYP2C19 inhibitor.
Dichlorphenamide: (Moderate) Use dichlorphenamide and amoxicillin together with caution. Dichlorphenamide increases potassium excretion and can cause hypokalemia and should be used cautiously with other drugs that may cause hypokalemia including amoxicillin. Measure potassium concentrations at baseline and periodically during dichlorphenamide treatment. If hypokalemia occurs or persists, consider reducing the dose or discontinuing dichlorphenamide therapy.
Dienogest; Estradiol valerate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Digoxin: (Minor) Displacement of penicillins from plasma protein binding sites by highly protein bound drugs like digoxin will elevate the level of free penicillin in the serum. The clinical significance of this interaction is unclear. It is recommended to monitor these patients for increased adverse effects.
Disopyramide: (Moderate) Monitor for an increase in disopyramide-related adverse reactions if coadministration with vonoprazan is necessary as concurrent use may increase disopyramide exposure. Disopyramide is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor. Although specific drug interaction studies have not been done for disopyramide, cases of life-threatening interactions have been reported when disopyramide was coadministered with moderate and strong CYP3A inhibitors.
Dofetilide: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with vonoprazan is necessary as concurrent use may increase dofetilide exposure. Vonoprazan is a weak CYP3A inhibitor. Dofetilide is a minor CYP3A substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A inhibitors may increase the risk of arrhythmia (torsade de pointes).
Dolutegravir; Rilpivirine: (Contraindicated) Concomitant use of vonoprazan with rilpivirine is contraindicated due to the potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Vonoprazan reduces intragastric acidity, which may decrease the absorption of rilpivirine reducing its efficacy.
Doxepin: (Moderate) Monitor for an increase in doxepin-related adverse reactions if concomitant use of vonoprazan is necessary. Concomitant use may increase doxepin exposure; doxepin is primarily metabolized by CYP2C19 and CYP2D6 and vonoprazan is a CYP2C19 inhibitor.
Doxycycline: (Minor) Consider additional monitoring or alternative antimicrobial therapy for patients with infections in which clinical response is highly dependent upon the rapid, bactericidal activity of penicillins. Bacterostatic antibacterials like tetracyclines may antagonize the bactericidal effects of penicillins which may reduce their efficacy. The clinical relevance of this interaction is poorly defined and for many infections the benefits of combination therapy are likely to outweigh the potential risks.
Drospirenone: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Drospirenone; Estetrol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Drospirenone; Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Drospirenone; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Efavirenz: (Major) Avoid concomitant use of vonoprazan and efavirenz due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concomitant use of vonoprazan and efavirenz due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid concomitant use of vonoprazan and efavirenz due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Elagolix: (Major) Avoid concomitant use of vonoprazan and elagolix due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and elagolix is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Elagolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of vonoprazan and elagolix due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and elagolix is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Eliglustat: (Major) Coadministration of eliglustat and vonoprazan is not recommended in poor CYP2D6 metabolizers (PMs). In extensive CYP2D6 metabolizers (EM) with mild hepatic impairment, coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. Eliglustat is a CYP3A and CYP2D6 substrate; vonoprazan is a weak CYP3A inhibitor. Because CYP3A plays a significant role in the metabolism of eliglustat in CYP2D6 PMs, coadministration of eliglustat with CYP3A inhibitors may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias).
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Contraindicated) Concomitant use of vonoprazan with rilpivirine is contraindicated due to the potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Vonoprazan reduces intragastric acidity, which may decrease the absorption of rilpivirine reducing its efficacy.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Contraindicated) Concomitant use of vonoprazan with rilpivirine is contraindicated due to the potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Vonoprazan reduces intragastric acidity, which may decrease the absorption of rilpivirine reducing its efficacy.
Encorafenib: (Major) Avoid concomitant use of vonoprazan and encorafenib due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A inducer.
Enzalutamide: (Major) Avoid concomitant use of vonoprazan and enzalutamide due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and enzalutamide is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Erlotinib: (Major) Avoid concomitant use of erlotinib and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of erlotinib reducing its efficacy.
Eslicarbazepine: (Major) Avoid concomitant use of vonoprazan and eslicarbazepine due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and eslicarbazepine is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Estradiol; Levonorgestrel: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Estradiol; Norethindrone: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Estradiol; Norgestimate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Ethacrynic Acid: (Minor) Ethacrynic acid may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. This combination should be used with caution and patients monitored for increased side effects.
Ethinyl Estradiol; Norelgestromin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Ethinyl Estradiol; Norethindrone Acetate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Ethinyl Estradiol; Norgestrel: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Ethynodiol Diacetate; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Etonogestrel; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Etravirine: (Major) Avoid concomitant use of vonoprazan and etravirine due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and etravirine is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Felodipine: (Moderate) Concurrent use of felodipine and vonoprazan should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A substrate and vonoprazan is a weak CYP3A inhibitor. Concurrent use of another weak CYP3A inhibitor increased felodipine AUC and Cmax by approximately 50%.
Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. If vonoprazan is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A substrate, and coadministration with CYP3A inhibitors like vonoprazan can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If vonoprazan is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Ferric Maltol: (Moderate) Monitor for decreased efficacy of oral iron salts if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of iron reducing its efficacy.
Finerenone: (Moderate) Monitor serum potassium during initiation or dose adjustment of either finerenone or vonoprazan; a finerenone dosage reduction may be necessary. Concomitant use may increase finerenone exposure and the risk of hyperkalemia. Finerenone is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor. Coadministration with another weak CYP3A inhibitor increased overall exposure to finerenone by 21%.
Flibanserin: (Moderate) The concomitant use of flibanserin and multiple weak CYP3A inhibitors, including vonoprazan, may increase flibanserin concentrations, which may increase the risk of flibanserin-induced adverse reactions. Therefore, patients should be monitored for hypotension, syncope, somnolence, or other adverse reactions, and the potential outcomes of combination therapy with multiple weak CYP3A inhibitors and flibanserin should be discussed with the patient.
Fosamprenavir: (Major) Avoid concomitant use of vonoprazan and fosamprenavir due to altered plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and fosamprenavir is both a strong CYP3A inhibitor and moderate CYP3A inducer. The net effect on CYP3A4 substrates is unclear. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Fosphenytoin: (Major) Avoid concomitant use of vonoprazan and fosphenytoin due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Concomitant use may also increase fosphenytoin concentrations. Vonoprazan is a CYP3A substrate and CYP2C19 inhibitor and fosphenytoin is a CYP2C19 substrate and strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Furosemide: (Minor) Furosemide may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. This combination should be used with caution and patients monitored for increased side effects.
Gefitinib: (Major) Avoid concomitant use of gefitinib and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of gefitinib reducing its efficacy.
Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like vonoprazan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If vonoprazan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like vonoprazan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If vonoprazan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like vonoprazan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If vonoprazan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. If vonoprazan is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with weak CYP3A inhibitors like vonoprazan can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If vonoprazan is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Indomethacin: (Minor) Indomethacin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. This combination should be used with caution and patients monitored for increased side effects.
Infigratinib: (Major) Avoid concomitant use of infigratinib and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of infigratinib reducing its efficacy.
Iron Salts: (Moderate) Monitor for decreased efficacy of oral iron salts if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of iron reducing its efficacy.
Iron: (Moderate) Monitor for decreased efficacy of oral iron salts if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of iron reducing its efficacy.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid concomitant use of vonoprazan and rifampin due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and rifampin is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Isoniazid, INH; Rifampin: (Major) Avoid concomitant use of vonoprazan and rifampin due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and rifampin is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Isradipine: (Moderate) Monitor for an increase in isradipine-related adverse reactions including hypotension if coadministration with vonoprazan is necessary. Concomitant use may increase isradipine exposure. Isradipine is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Itraconazole: (Moderate) Administer vonoprazan at least 2 hours before or 2 hours after itraconazole 100 mg capsules. Monitor for increased itraconazole-related adverse effects if vonoprazan is administered with itraconazole 65 mg capsules; a dose reduction may be needed. Drugs that reduce gastric acidity, such as vonoprazan, may decrease the systemic exposure of the 100 mg itraconazole capsule formulation. Conversely, exposure to itraconazole is increased when gastric acid reducers are administered with the 65 mg itraconazole capsule.
Ixabepilone: (Moderate) Monitor for ixabepilone toxicity and reduce the ixabepilone dose as needed if concurrent use of vonoprazan is necessary. Concomitant use may increase ixabepilone exposure and the risk of adverse reactions. Ixabepilone is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Ketoconazole: (Major) Avoid concomitant use of ketoconazole and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of ketoconazole reducing its efficacy.
Ledipasvir; Sofosbuvir: (Major) Avoid concomitant use of ledipasvir and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of ledipasvir reducing its efficacy.
Lemborexant: (Major) Limit the dose of lemborexant to 5 mg PO once daily if coadministered with vonoprazan as concomitant use may increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A substrate; vonoprazan is a weak CYP3A inhibitor. Coadministration with a weak CYP3A inhibitor is predicted to increase lemborexant exposure by less than 2-fold.
Leuprolide; Norethindrone: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Levoketoconazole: (Major) Avoid concomitant use of ketoconazole and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of ketoconazole reducing its efficacy.
Levonorgestrel: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Levonorgestrel; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Moderate) Monitor for decreased efficacy of oral iron salts if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of iron reducing its efficacy.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Moderate) Monitor for decreased efficacy of oral iron salts if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of iron reducing its efficacy.
Levothyroxine: (Moderate) Monitor for altered response to thyroid hormones if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of oral thyroid hormones reducing their efficacy.
Levothyroxine; Liothyronine (Porcine): (Moderate) Monitor for altered response to thyroid hormones if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of oral thyroid hormones reducing their efficacy.
Levothyroxine; Liothyronine (Synthetic): (Moderate) Monitor for altered response to thyroid hormones if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of oral thyroid hormones reducing their efficacy.
Lidocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with vonoprazan is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Lidocaine; Epinephrine: (Moderate) Monitor for lidocaine toxicity if coadministration with vonoprazan is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Lidocaine; Prilocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with vonoprazan is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Liothyronine: (Moderate) Monitor for altered response to thyroid hormones if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of oral thyroid hormones reducing their efficacy.
Lomitapide: (Major) Decrease the dose of lomitapide by one-half not to exceed 30 mg/day PO if coadministration with vonoprazan is necessary. Concomitant use may significantly increase the serum concentration of lomitapide. Vonoprazan is a weak CYP3A inhibitor; the exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A inhibitors.
Lonafarnib: (Major) Avoid coadministration of lonafarnib and vonoprazan; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions. Resume previous lonafarnib dosage 14 days after discontinuing vonoprazan. Lonafarnib is a sensitive CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Lorlatinib: (Major) Avoid concomitant use of vonoprazan and lorlatinib due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and lorlatinib is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Lumacaftor; Ivacaftor: (Major) Avoid concomitant use of vonoprazan and lumacaftor; ivacaftor due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and lumacaftor; ivacaftor is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Lumacaftor; Ivacaftor: (Major) Avoid concomitant use of vonoprazan and lumacaftor; ivacaftor due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and lumacaftor; ivacaftor is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Mafenide: (Minor) Sulfonamides may compete with amoxicillin for renal tubular secretion, increasing amoxicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
Magnesium Salicylate: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as penicillins, and sulfonamides. An enhanced effect of the displaced drug may occur.
Mavacamten: (Major) Reduce the mavacamten dose by 1 level (i.e., 15 to 10 mg, 10 to 5 mg, or 5 to 2.5 mg) in patients receiving mavacamten and starting vonoprazan therapy. Avoid initiation of vonoprazan in patients who are on stable treatment with mavacamten 2.5 mg per day because a lower dose of mavacamten is not available. Initiate mavacamten at the recommended starting dose of 5 mg PO once daily in patients who are on stable vonoprazan therapy. Concomitant use increases mavacamten exposure, which may increase the risk of adverse drug reactions. Mavacamten is a CYP2C19 substrate and vonoprazan is a weak CYP2C19 inhibitor. Concomitant use with another weak CYP2C19 inhibitor in CYP2C19 normal and rapid metabolizers increased overall mavacamten exposure by 48%.
Mefloquine: (Moderate) Use mefloquine with caution if coadministration with vonoprazan is necessary as concurrent use may increase mefloquine exposure and mefloquine-related adverse events. Mefloquine is a substrate of CYP3A and vonoprazan is a weak CYP3A inhibitor.
Meperidine: (Moderate) Consider a reduced dose of meperidine with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. If vonoprazan is discontinued, meperidine plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to meperidine. Meperidine is a substrate of CYP3A and vonoprazan is a weak CYP3A inhibitor. Concomitant use with vonoprazan can increase meperidine exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of meperidine.
Methadone: (Moderate) Consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. If vonoprazan is discontinued, methadone plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to methadone. Methadone is a substrate of CYP3A, CYP2B6, CYP2C19, CYP2C9, and CYP2D6; vonoprazan is a weak CYP3A and CYP2C19 inhibitor. Concomitant use with vonoprazan can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone.
Methohexital: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Methotrexate: (Major) Avoid concomitant use of methotrexate with penicillins due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions.
Midazolam: (Moderate) Use caution when midazolam is coadministered with vonoprazan. Concurrent use may increase midazolam exposure leading to prolonged sedation. Midazolam is a sensitive CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Minocycline: (Minor) Consider additional monitoring or alternative antimicrobial therapy for patients with infections in which clinical response is highly dependent upon the rapid, bactericidal activity of penicillins. Bacterostatic antibacterials like tetracyclines may antagonize the bactericidal effects of penicillins which may reduce their efficacy. The clinical relevance of this interaction is poorly defined and for many infections the benefits of combination therapy are likely to outweigh the potential risks.
Mitotane: (Major) Avoid concomitant use of vonoprazan and mitotane due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and mitotane is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Mycophenolate: (Moderate) Drugs that alter the gastrointestinal flora may interact with mycophenolate by disrupting enterohepatic recirculation. Amoxicillin;Clavulanic Acid may decrease normal GI flora levels and thus lead to less free mycophenolate available for absorption. The effect of amoxicillin without clavulantic acid on mycophenolate kinetics is unclear. (Moderate) Monitor for altered mycophenolate efficacy when coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of mycophenolate reducing its efficacy.
Nafcillin: (Major) Avoid concomitant use of vonoprazan and nafcillin due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and nafcillin is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Nanoparticle Albumin-Bound Sirolimus: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 during concomitant use of vonoprazan. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Nelfinavir: (Major) Avoid concomitant use of nelfinavir and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of nelfinavir reducing its efficacy.
Neratinib: (Major) Avoid concomitant use of neratinib and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of neratinib reducing its efficacy.
Nilotinib: (Major) Avoid concomitant use of nilotinib and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of nilotinib reducing its efficacy.
Nimodipine: (Moderate) Monitor blood pressure and reduce the dose of nimodipine as clinically appropriate if coadministration with vonoprazan is necessary. Concurrent use may increase nimodipine exposure. Nimodipine is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with vonoprazan due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A substrate and vonoprazan is a CYP3A inhibitor. Coadministration with another CYP3A inhibitor increased the AUC of nisoldipine by 30% to 45%.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Moderate) Monitor for decreased efficacy of oral iron salts if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of iron reducing its efficacy.
Norethindrone: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Norethindrone; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Moderate) Monitor for decreased efficacy of oral iron salts if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of iron reducing its efficacy.
Norgestimate; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Norgestrel: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Octreotide: (Moderate) Concomitant use of oral octreotide with vonoprazan may require increased doses of octreotide. Vonoprazan reduces intragastric acidity, which may decrease the absorption of oral octreotide reducing its efficacy.
Omadacycline: (Minor) Consider additional monitoring or alternative antimicrobial therapy for patients with infections in which clinical response is highly dependent upon the rapid, bactericidal activity of penicillins. Bacterostatic antibacterials like tetracyclines may antagonize the bactericidal effects of penicillins which may reduce their efficacy. The clinical relevance of this interaction is poorly defined and for many infections the benefits of combination therapy are likely to outweigh the potential risks.
Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid concomitant use of vonoprazan and rifabutin due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and rifabutin is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Oral Contraceptives: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. If vonoprazan is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with weak CYP3A inhibitors like vonoprazan can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If vonoprazan is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Pazopanib: (Major) Avoid concomitant use of pazopanib and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of pazopanib reducing its efficacy.
Pentobarbital: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Pexidartinib: (Major) Avoid concomitant use of vonoprazan and pexidartinib due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Additionally, vonoprazan reduces intragastric acidity, which may decrease the absorption of pexidartinib reducing its efficacy. Vonoprazan is a CYP3A substrate and pexidartinib is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Phenobarbital: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Phenytoin: (Major) Avoid concomitant use of vonoprazan and phenytoin due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Concomitant use may also increase phenytoin concentrations. Vonoprazan is a CYP3A substrate and CYP2C19 inhibitor and phenytoin is a CYP2C19 substrate and strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Pimozide: (Major) Avoid concomitant use of pimozide and vonoprazan. Concomitant use may result in elevated pimozide concentrations resulting in QT prolongation, ventricular arrhythmias, and sudden death. Pimozide is CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Polysaccharide-Iron Complex: (Moderate) Monitor for decreased efficacy of oral iron salts if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of iron reducing its efficacy.
Primidone: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Probenecid: (Minor) Probenecid competitively inhibits renal tubular secretion and causes higher, prolonged serum levels of penicillins. In general, this pharmacokinetic interaction is not harmful and can be used therapeutically if needed.
Probenecid; Colchicine: (Minor) Probenecid competitively inhibits renal tubular secretion and causes higher, prolonged serum levels of penicillins. In general, this pharmacokinetic interaction is not harmful and can be used therapeutically if needed.
Propafenone: (Moderate) Monitor for increased propafenone toxicity if coadministered with vonoprazan; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and vonoprazan with a CYP2D6 inhibitor or in patients with CYP2D6 deficiency. Propafenone is a CYP3A and CYP2D6 substrate and vonoprazan is a weak CYP3A inhibitor.
Relugolix; Estradiol; Norethindrone acetate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Repotrectinib: (Major) Avoid concomitant use of vonoprazan and repotrectinib due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and repotrectinib is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A inducer.
Rifabutin: (Major) Avoid concomitant use of vonoprazan and rifabutin due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and rifabutin is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Rifampin: (Major) Avoid concomitant use of vonoprazan and rifampin due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and rifampin is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Rifapentine: (Major) Avoid concomitant use of vonoprazan and rifapentine due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and rifapentine is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Rilpivirine: (Contraindicated) Concomitant use of vonoprazan with rilpivirine is contraindicated due to the potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Vonoprazan reduces intragastric acidity, which may decrease the absorption of rilpivirine reducing its efficacy.
Risedronate: (Major) Avoid concomitant use of vonoprazan with delayed-release risedronate tablets (Atelvia). Concomitant use of drugs that raise gastric pH, such as vonoprazan, increases risedronate bioavailability due to faster release of the drug from the enteric coated tablet. This interaction does not apply to risedronate immediate-release tablets.
Salsalate: (Minor) Due to high protein binding, salicylates could be displaced from binding sites or could displace other highly protein-bound drugs such as penicillins. An enhanced effect of the displaced drug may occur.
Sarecycline: (Minor) Consider additional monitoring or alternative antimicrobial therapy for patients with infections in which clinical response is highly dependent upon the rapid, bactericidal activity of penicillins. Bacterostatic antibacterials like tetracyclines may antagonize the bactericidal effects of penicillins which may reduce their efficacy. The clinical relevance of this interaction is poorly defined and for many infections the benefits of combination therapy are likely to outweigh the potential risks.
Secobarbital: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Segesterone Acetate; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Selpercatinib: (Major) Avoid concomitant use of selpercatinib and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of selpercatinib reducing its efficacy.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of vonoprazan. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Sodium Benzoate; Sodium Phenylacetate: (Moderate) Antibiotics that undergo tubular secretion such as penicillins may compete with phenylacetlyglutamine and hippuric acid for active tubular secretion. The overall usefulness of sodium benzoate; sodium phenylacetate is due to the excretion of its metabolites. An increase in metabolite concentrations could contribute to failed treatment and worsening of the patient's clinical status. This combination should be used with caution.
Sodium Ferric Gluconate Complex; ferric pyrophosphate citrate: (Moderate) Monitor for decreased efficacy of oral iron salts if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of iron reducing its efficacy.
Sodium picosulfate; Magnesium oxide; Anhydrous citric acid: (Major) Prior or concomitant use of antibiotics with sodium picosulfate; magnesium oxide; anhydrous citric acid may reduce efficacy of the bowel preparation as conversion of sodium picosulfate to its active metabolite bis-(p-hydroxy-phenyl)-pyridyl-2-methane (BHPM) is mediated by colonic bacteria. If possible, avoid coadministration. Certain antibiotics (i.e., tetracyclines and quinolones) may chelate with the magnesium in sodium picosulfate; magnesium oxide; anhydrous citric acid solution. Therefore, these antibiotics should be taken at least 2 hours before and not less than 6 hours after the administration of sodium picosulfate; magnesium oxide; anhydrous citric acid solution.
Sofosbuvir; Velpatasvir: (Major) Avoid concomitant use of velpatasvir and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of velpatasvir reducing its efficacy. Velpatasvir solubility decreases as pH increases; therefore, drugs that increase gastric pH are expected to decrease the concentrations of velpatasvir, potentially resulting in loss of antiviral efficacy.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid concomitant use of velpatasvir and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of velpatasvir reducing its efficacy. Velpatasvir solubility decreases as pH increases; therefore, drugs that increase gastric pH are expected to decrease the concentrations of velpatasvir, potentially resulting in loss of antiviral efficacy.
Sotorasib: (Major) Avoid concomitant use of vonoprazan and sotorasib due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Additionally, vonoprazan reduces intragastric acidity, which may decrease the absorption of sotorasib reducing its efficacy. Vonoprazan is a CYP3A substrate and sotorasib is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
St. John's Wort, Hypericum perforatum: (Major) Avoid concomitant use of vonoprazan and St. John's Wort due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if vonoprazan must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. If vonoprazan is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A substrate, and coadministration with a weak CYP3A inhibitor like vonoprazan can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If vonoprazan is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
Sulfadiazine: (Minor) Sulfonamides may compete with amoxicillin for renal tubular secretion, increasing amoxicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Minor) Sulfonamides may compete with amoxicillin for renal tubular secretion, increasing amoxicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
Sulfasalazine: (Minor) Sulfonamides may compete with amoxicillin for renal tubular secretion, increasing amoxicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
Sulfonamides: (Minor) Sulfonamides may compete with amoxicillin for renal tubular secretion, increasing amoxicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
Tacrolimus: (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with vonoprazan is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; vonoprazan is a weak CYP3A inhibitor.
Tetracycline: (Minor) Consider additional monitoring or alternative antimicrobial therapy for patients with infections in which clinical response is highly dependent upon the rapid, bactericidal activity of penicillins. Bacterostatic antibacterials like tetracyclines may antagonize the bactericidal effects of penicillins which may reduce their efficacy. The clinical relevance of this interaction is poorly defined and for many infections the benefits of combination therapy are likely to outweigh the potential risks.
Tetracyclines: (Minor) Consider additional monitoring or alternative antimicrobial therapy for patients with infections in which clinical response is highly dependent upon the rapid, bactericidal activity of penicillins. Bacterostatic antibacterials like tetracyclines may antagonize the bactericidal effects of penicillins which may reduce their efficacy. The clinical relevance of this interaction is poorly defined and for many infections the benefits of combination therapy are likely to outweigh the potential risks.
Thyroid hormones: (Moderate) Monitor for altered response to thyroid hormones if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of oral thyroid hormones reducing their efficacy.
Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with vonoprazan is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of vonoprazan, a weak CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Tramadol; Acetaminophen: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with vonoprazan is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of vonoprazan, a weak CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Triazolam: (Moderate) Monitor for signs of triazolam toxicity during coadministration with vonoprazan. Coadministration may increase the exposure of triazolam. Consider appropriate dose reduction of triazolam when coadministered with weak CYP3A inhibitors, as clinically indicated. Triazolam is a sensitive CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Typhoid Vaccine: (Major) Antibiotics which possess bacterial activity against salmonella typhi organisms may interfere with the immunological response to the live typhoid vaccine. Allow 24 hours or more to elapse between the administration of the last dose of the antibiotic and the live typhoid vaccine.
Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with vonoprazan. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with vonoprazan is necessary. Vinorelbine is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with vonoprazan is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. The R-enantiomer of warfarin is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. (Moderate) The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Vonoprazan and amoxicillin are used together to eradicate Helicobacter pylori infection. Amoxicillin has demonstrated in vitro activity against most susceptible strains of H. pylori. Vonoprazan appears to have some in vitro activity against H. pylori but the clinical significance of this finding has not been established. A combination therapy regimen is necessary for successful eradication of H. pylori and to avoid the development of resistance. The relative contribution of systemic versus local antimicrobial activity against H. pylori for the components of vonoprazan; amoxicillin dual pack therapy has not been established. Acid suppression enhances the replication of H. pylori bacteria and the stability and effectiveness of antimicrobials in the treatment of H. pylori infection.
-Vonoprazan: Vonoprazan is a potassium-competitive acid blocker (PCAB). Vonoprazan suppresses basal and stimulated gastric acid secretion at the secretory surface of the gastric parietal cell through inhibition of the H+, K+-ATPase enzyme system in a potassium competitive manner. Because this enzyme is regarded as the acid (proton) pump within the parietal cell, vonoprazan has been characterized as a type of gastric proton-pump inhibitor, in that it blocks the final step of acid production. Vonoprazan does not require activation by acid. Vonoprazan may selectively concentrate in the parietal cells in both the resting and stimulated states. Vonoprazan binds to the active proton pumps in a noncovalent and reversible manner. Following a single 20 mg dose of vonoprazan, the onset of the antisecretory effect as measured by intragastric pH occurs within 2 to 3 hours. The elevated intragastric pH compared to placebo is maintained for over 24-hours after dosing. At a dose 6 times the maximum recommended dose, vonoprazan does not prolong the QT interval to any clinically relevant extent.
-Amoxicillin: Amoxicillin is a penicillin class antibacterial drug. It is similar to penicillin in its bactericidal action against susceptible bacteria during the stage of active multiplication. It acts through the inhibition of cell wall biosynthesis that leads to the death of the bacteria. Resistance to amoxicillin is mediated primarily through enzymes called beta-lactamases that cleave the beta-lactam ring of amoxicillin, rendering it inactive. Beta-lactam antibiotics such as amoxicillin are mainly bactericidal. Like other penicillins, amoxicillin inhibits the third and final stage of bacterial cell wall synthesis by preferentially binding to specific penicillin-binding proteins (PBPs) that are located inside the bacterial cell wall. Penicillin-binding proteins are responsible for several steps in the synthesis of the cell wall and are found in quantities of several hundred to several thousand molecules per bacterial cell. Penicillin-binding proteins vary among different bacterial species. Thus, the intrinsic activity of amoxicillin, as well as the other penicillins, against a particular organism depends on their ability to gain access to and bind with the necessary PBP. The aminopenicillins are able to penetrate gram-negative bacteria more readily than are the natural penicillins or penicillinase-resistant penicillins due to the presence of a free amino group within the structure. Like all beta-lactam antibiotics, the ability of amoxicillin to interfere with PBP-mediated cell wall synthesis ultimately leads to cell lysis. Lysis is mediated by bacterial cell wall autolytic enzymes (i.e., autolysins). The relationship between PBPs and autolysins is unclear, but it is possible that the beta-lactam antibiotic interferes with an autolysin inhibitor.
The components of the product (vonoprazan tablets and amoxicillin capsules) are administered orally. The pharmacokinetics of the individual drugs when coadministered have not been studied. Studies have shown no clinically significant interactions of vonoprazan and amoxicillin when administered together. The systemic pharmacokinetic information below is based on administration of each agent alone.
-Vonoprazan: Plasma-protein binding of vonoprazan ranged from 85% to 88% in healthy subjects and was independent of concentration from 0.1 to 10 mcg/mL. Vonoprazan is metabolized in the liver to inactive metabolites via multiple pathways by a combination of cytochrome P450 (CYP) isoenzymes (CYP3A4/5, CYP2B6, CYP2C19, CYP2C9 and CYP2D6) along with sulfo- and glucuronosyl-transferases. CYP2C19 polymorphisms have been evaluated in clinical studies and there were no considerable differences in the pharmacokinetics of vonoprazan based on CYP2C19 metabolizer status. Following oral administration of radiolabeled vonoprazan, approximately 67% of the radiolabeled dose (8% as unchanged vonoprazan) was recovered in urine and 31% (1.4% as unchanged vonoprazan) was recovered in feces.
-Amoxicillin: Amoxicillin diffuses readily into most body tissues and fluids, except for brain and spinal fluid, where the drug only passes if meninges are inflamed. In blood serum, amoxicillin is approximately 20% protein-bound. Following a 1-gram dose and utilizing a special skin window technique to determine levels of the antibacterial, it was noted that therapeutic levels were found in the interstitial fluid. Approximately 60% of an orally administered dose of amoxicillin is excreted in the urine unchanged within 6 to 8 hours. Detectable serum levels are observed up to 8 hours after an orally administered dose of amoxicillin. Since most of the amoxicillin is excreted unchanged in the urine, its excretion can be delayed by concurrent administration of probenecid. In patients with normal renal function, the elimination half-life of amoxicillin is 61.3 minutes.
Affected cytochrome P450 isoenzymes and drug transporters: CYP2C19, CYP3A4/5, CYP2B6, MATE1, and OCT1
In vitro studies have shown that vonoprazan directly and time-dependently inhibits CYP2C19, CYP3A4/5, and CYP2B6. Vonoprazan is a CYP2C19 inhibitor that can produce clinically significant interactions with medications metabolized or activated by this enzyme. Vonoprazan is a weak CYP3A inhibitor and may increase exposure to sensitive CYP3A4 substrates of narrow therapeutic index. Vonoprazan also inhibits multidrug and toxin extrusion protein 1 (MATE1) and organic cation transporter 1 (OCT1), but only at concentrations higher than clinically relevant. Strong or moderate CYP3A inducers may decrease vonoprazan exposure.
Vonoprazan may also exhibit clinically significant drug interactions by reducing intragastric acidity, which may alter the absorption of certain drugs leading to changes in their safety and/or effectiveness.
-Route-Specific Pharmacokinetics
Oral Route
-Vonoprazan: Vonoprazan exhibits time independent pharmacokinetics and steady-state concentrations are achieved by Day 3 to 4. After multiple doses of vonoprazan ranging from 10 mg to 40 mg once daily for 7 days in healthy subjects, the Cmax and AUC values for vonoprazan increased in an approximately dose-proportional manner. Steady-state mean plasma exposure of vonoprazan following 20 mg twice daily dosing was approximately 1.8-fold higher compared to Day 1. Administration with a high-fat meal resulted in a 5% increase in Cmax, a 15% increase in AUC, and a delay in median time to maximum concentration (Tmax) of 2 hours. These changes are not considered to be clinically significant.
-Amoxicillin: Amoxicillin is stable in the presence of gastric acid and is rapidly absorbed after oral administration. Doses of 500-mg amoxicillin capsules result in average peak blood levels 1 to 2 hours after administration in the range of 5.5 mcg/mL to 7.5 mcg/mL, respectively.
-Special Populations
Hepatic Impairment
-Vonoprazan: Vonoprazan serum concentrations are increased in patients with hepatic impairment. In patients with mild (Child-Pugh Class A), moderate (Child-Pugh Class B), or severe (Child-Pugh Class C) hepatic impairment, there was an approximate 1.2-, 2.4- and 2.6-times greater respectively in mean AUC compared to normal subjects. Protein binding of vonoprazan is not affected by impaired hepatic function.
-Amoxicillin: Amoxicillin pharmacokinetics are not altered by hepatic impairment.
Renal Impairment
-Vonoprazan: Vonoprazan systemic exposure (AUC) increased by 1.7 times, 1.3-times, and 2.4-times in patients with mild, moderate, and severe renal impairment when compared to patients with normal renal function. The AUC estimates were 1.3-fold greater when compared to patients with normal renal function for patients requiring dialysis. Protein binding of vonoprazan is not affected by impaired renal function. Vonoprazan was present in the dialysate and represented 0.94% of the dose administered in patients requiring dialysis. The use of vonoprazan should be avoided in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2).
-Amoxicillin: Amoxicillin is mostly eliminated unchanged by the kidneys and elimination half-life increases as renal function declines. Studies in adult patients have shown that the elimination half-life of amoxicillin is prolonged to approximately 10 to 13 hours in patients with end-stage renal disease. Dosage adjustments are recommended in patients with severe renal impairment, and thus, the fixed-dose dual co-packaged product of vonoprazan; amoxicillin should be avoided in patients with an eGFR less than 30 mL/min/1.73 m2.
Gender Differences
There were no clinically significant differences in the pharmacokinetics of vonoprazan based on sex or gender.
Ethnic Differences
There were no clinically significant differences in the pharmacokinetics of vonoprazan based on race or ethnicity.